Therapeutic compounds

ABSTRACT

The present invention relates to compounds that are antagonists of the orexin-1 receptor. The compounds have the structural formula (I) defined herein. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of diseases or disorders associated with orexin-1 receptor activity.

INTRODUCTION

The present invention relates to therapeutic compounds. Morespecifically, the present invention relates to compounds that areinhibitors of the orexin-1 receptor. The present invention also relatesto processes for the preparation of these compounds, to pharmaceuticalcompositions comprising them, and to their use in the treatment ofdiseases or disorders associated with orexin-1 receptor activity.

BACKGROUND OF THE INVENTION

The neuropeptides Orexin-A (OxA) and Orexin-B (OxB) (also known asHypocretin-1 and Hypocretin-2) originate from the same prepro-peptide,which is expressed exclusively in the hypothalamus (1). Cleavage of theprepro-peptide (prepro-orexin) yields OxA a 33 amino acid polypeptidewhich is extensively post-translationally modified (C-terminalamidation, N-terminally cyclised with a pyroglutamyl residue). OxAshares a 46% sequence identity with OxB which is a 28 amino acid,C-terminally amidated linear polypeptide which likely forms a helicalsecondary structure (3).

The fully functional mature peptide neurotransmitters act as agonists onthe orexin-1 (OX₁) and orexin-2 (OX2) 7-transmembrane G-protein coupledreceptors (also known as HCRTR1 and HCRTR2) that, like the orexinneuropeptides, share a high sequence homology across species (2, 6). OX₁binds both OxA and OxB, albeit, with differential affinity (OxAhas >10-fold higher affinity than OxB). On the contrary OX2, whichshares a 64% sequence identity with OX₁, binds both polypeptides withnearly equivalent affinity (2). The primary G-protein mediated mechanismthrough which both receptors act is G_(q/11) activation of phospholipaseC catalysing the liberation of inositol-1,4,5-triphosphate (IP₃), whichin turn acts on IP₃ receptors to release calcium from intracellularstores. OX₂ has also been reported to modulate cAMP levels viaactivation of G_(s) and G_(i) and OX₁ appears capable of signallingthrough G_(i/o) to also modulate cAMP levels (5, 8). The high degree ofsequence similarity in the peptides and receptors across speciestranslates into similar in vitro pharmacology (7).

The hypothalamus, where orexin is predominately expressed, regulates abroad array of physiological and behavioural activities. Orexinexpression in this brain structure has been mapped immunohistochemicallyto only a very restricted number of neurons that reside specifically inthe perifornical (50%), lateral and dorsomedial areas (4). Theprojection fields of these neurons have been identified in numerousbrain regions, including the cortex, thalamus, hypothalamus, brainstem,and spinal cord, but not the cerebellum (9). This extensive coverage ofthe brain suggests that the orexin ligand/receptor system is implicateddirectly or indirectly in the regulation of multiple brain functions.Notably, knockout experiments in mice suggested that the orexin systemis a key regulator of behavioural arousal, sleep and wakefulness.Indeed, the observed phenotype in orexin knockout mice was very similarto that of narcolepsy in humans (10, 11). Narcolepsy in humans is achronic and disabling disorder characterized by excessive sleepinessduring the day, fragmented sleep and cataplexy. Studies in dogs havelinked the cause of the disorder to the disruption of the OX₂ gene or aloss of orexin peptide expression (12). Further supporting evidence thatin particular the disruption of OX₂ function and or the absence ofmature OxB ligand are associated with narcolepsy came from studies inknock-out mice (17). Subsequent clinical studies comparing the levels ofOxA in the cerebrospinal fluid of narcoleptic patients to normalindividuals confirmed that the disruption of the orexin system shows acausal relationship with the occurrence of narcolepsy in humans (13).Additional studies in unusual early onset human narcolepsy resulted inthe identification of a mutation in the orexin gene that furtherstrengthened the link between narcolepsy and the orexin system in humans(14). More recently, clinical data demonstrating the pharmacologicalrelevance of the orexins in CNS disorders has emerged. Most notably,clinical trials with small molecule dual OX₁ and OX₂ antagonists (DORAs)such as BELSOMRA® (Suvorexant), have clearly demonstrated the potentialutility of such agents in treating sleep disorders (15, 16, 18). Thesedata together with the pre-clinical evidence presented above clearlyimplicate OX₂ in sleep regulation.

The differential brain expression of OX₁ and OX₂ coupled with thediversity of neuro-biological effects attributed to the orexins stronglysuggests drugs modulating OX₁ or OX₂ will elicit different biologicaleffects. To this end, recent reports linking the OX₁/OxA systemspecifically to feeding and behavioural disorders are important.

Given that prepro-orexin mRNA levels are mainly found in the lateral andposterior hypothalamus, areas of the brain classically implicated in theregulation of food intake and energy balance/body weight, a link betweenthe orexin system and feeding behaviour is not unexpected (19). The roleof the OX₁/OxA system in such functions has been strengthened by aseries of pre-clinical studies. Thus intracerebroventricular (i.c.v.)administration of OxA (20) has been shown to induce feeding and specificanti-orexin antibodies dose-dependently suppress food intake (21). Inparticular, the latter study indicates that orexin receptor antagonistsshould have a beneficial effect on orexin stimulated feeding. Thishypothesis is supported by independent in vivo studies, which clearlyidentify OX₁ as the dominant receptor of the orexin system in theregulation of food intake and energy balance. Thus, experimentsconducted with selective OX₁ and OX₂ receptor antagonists have shownthat OX₁ selective compounds alter food intake and energy balance incircumstances of concurrent exposure to stress (22, 23). The dominanteffect of the OX₁ on regulating feeding behaviour and energy balance isfurther supported by observations which show that OX₁ expression isselectively up-regulated in response to fasting, whereas those of OX₂are unaffected (24). Finally, studies with an OX₁ specific antibodystrongly suggests that a selective OX₁ antagonist should suppress foodintake and thus have potential therapeutic utility for the treatment offeeding related disorders such as binge eating or obesity.

Elevated OX₁ levels have also been associated with psychiatricconditions including schizophrenia, anxiety and mood disorders, panicattacks, reward seeking behaviours and addiction (25, 26, 27). Studieswith selective OX₁ antagonists (SB334867, SB408124) clearly demonstrateda beneficial effect in a clinically relevant animal model of panic thusimplying that OX₁ antagonist could provide a novel therapeutic approachfor the treatment of panic disorders (27).

Indirect evidence for the involvement of the orexin system in rewardseeking behaviour comes from studies which show that orexinergic neuronsproject to reward associated brain regions such as the nucleus accumbensand ventral tegmental area (28). Direct experimental evidence comes fromstudies involving the intracerebroventricular (icv) infusion of orexin,which led to a dose-dependent reinstatement of cocaine seeking. The workby Boutrel et. al. also links stress pathways to the effect of orexin onaddiction and reward (29). Notably, stress is considered a prominentstimulus for relapse in abstinent addicts (31). The link between stress,addiction and orexin was further strengthened by pharmacological studiesin a foot-shock model. These showed activation of orexin neurons inspecific areas of the posterior and dorsomedial hypothalamus, which areparticularly associated with stress but not the lateral hypothalamus,which has a strong link to reward (32). Moreover orexin as a mediator ofstress-induced reinstatement of addictive behaviour was also shown foralcohol seeking (30). Importantly the effects of stress inducedreinstatement of alcohol and cocaine seeking in animal models can beattenuated with the selective OX₁ antagonist SB334867 supporting thetherapeutic use of OX₁ selective antagonists in these conditions (29,30).

Finally the Orexin/OX₁ pathway has been implicated in nicotineself-administration (33, 34) and re-instatement of nicotine seeking (35,36). Such data suggest that OX₁ antagonists could find utility assmoking cessation therapies.

Taken together the orexin system, and in particular the OX₁ pathway, maybe considered a target for the treatment of reward seeking behaviours,addiction and related disorders.

WO2003/051872 discloses certain heterocyclic-substituted ethylenediamine derivatives that act as antagonists of orexin-1 (OX₁) andorexin-2 (OX₂) receptors.

There is, however, a need for compounds that are potent inhibitors oforexin-1 (OX₁) activity and which show selectivity for inhibitingorexin-1 (OX₁) receptors over orexin-2 (OX₂) receptors. This profilewould provide effective therapeutic benefit for the treatment ofaddictive disorders in the absence of activity on the sleep-wake cycle.There is also a need for compounds that exhibit increased residencytimes at the orexin-1 (OX₁) receptor, and in particular, compounds thatpossess increased residency times at the orexin-1 (OX₁) receptorrelative to their residency times at the orexin-2 (OX₂) receptor.Increasing evidence suggests that the time molecules reside at theircellular target can provide an important indicator of their clinicalperformance (37) and it is potentially advantageous when developingantagonists of G protein coupled receptors to identify compounds whichexhibit slow dissociation from the receptor (38). Furthermore, thisincreased residence time at the receptor may provide extended durationof action in the clinical setting. Prolonged Orexin-1 antagonistreceptor blockade in the absence of prolonged blockade of the Orexin-2receptor therefore represents a new and potentially powerful approachfor the treatment of addictive disorders.

In addition, there is a need for compounds that have one or morefavourable pharmaceutical properties (e.g. favourable solubility, highmetabolic stability, low propensity for drug-drug interactions, lowpropensity for off-target pharmacological activity, sufficientpharmacokinetic profiles, good oral bioavailability, high therapeuticindex, lack of genotoxicity) that render them suitable for furtherdevelopment as candidate drugs. More specifically, for the treatment ofCNS disorders such as the disorders described herein, there is a needfor compounds that have favourable blood-brain barrier penetration andcompounds that achieve significant Orexin-1 receptor occupancy in thebrain following oral administration. Compounds that demonstrate thislevel of significant target engagement in the brain would be effected toshow significant efficacy in Orexin-1 receptor mediated CNS disorders.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a compound, or apharmaceutically acceptable salt or solvate thereof as defined herein.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of the invention as defined herein, ora pharmaceutically acceptable salt or solvate thereof, and one or morepharmaceutically acceptable excipients.

In another aspect, the present invention relates to a compound of theinvention as defined herein, or a pharmaceutically acceptable salt orsolvate thereof, or a pharmaceutical composition as defined herein, foruse in therapy.

In another aspect, the present invention relates to a compound of theinvention as defined herein, or a pharmaceutically acceptable salt orsolvate thereof, or a pharmaceutical composition as defined herein, foruse in the treatment of diseases or conditions in which orexin-1 (OX₁)activity is implicated.

In another aspect, the present invention relates to the use of acompound of the invention as defined herein, or a pharmaceuticallyacceptable salt or solvate thereof, in the manufacture of a medicamentfor use in the treatment of diseases or conditions in which orexin-1(OX₁) activity is implicated.

In another aspect, the present invention relates to a method of treatinga disease or condition in which orexin-1 (OX₁) activity is implicated,said method comprising administering to a subject in need of suchtreatment a therapeutically effective amount of a compound of theinvention as defined herein, or a pharmaceutically acceptable salt orsolvate thereof, or a pharmaceutical composition as defined herein.

Examples of conditions in which orexin-1 (OX₁) activity is implicatedinclude behavioural arousal, eating disorders (e.g. binge eating,obesity), psychiatric conditions (e.g. schizophrenia, anxiety, mooddisorders, reward seeking behaviours, alcohol or drug (e.g. nicotine)addiction, panic disorders (such as panic attacks) and/or anxiety).

In another aspect, the present invention provides a compound, or apharmaceutically acceptable salt or solvate thereof, or a pharmaceuticalcomposition as defined herein, for use in the treatment of behaviouralarousal, eating disorders (e.g. binge eating, obesity), psychiatricconditions (e.g. schizophrenia, anxiety, mood disorders, reward seekingbehaviours, alcohol or drug (e.g. nicotine) addiction, panic disorders(such as panic attacks) and/or anxiety).

In another aspect, the present invention provides the use of a compound,or a pharmaceutically acceptable salt or solvate thereof, in themanufacture of a medicament for use in the treatment of behaviouralarousal, eating disorders (e.g. binge eating, obesity), psychiatricconditions (e.g. schizophrenia, anxiety, mood disorders, reward seekingbehaviours, alcohol or drug (e.g. nicotine) addiction, panic disorders(such as panic attacks) and/or anxiety).

In another aspect, the present invention provides a method of treatingbehavioural arousal, eating disorders (e.g. binge eating, obesity),psychiatric conditions (e.g. schizophrenia, anxiety, mood disorders,reward seeking behaviours, alcohol or drug (e.g. nicotine) addiction,panic disorders (such as panic attacks) and/or anxiety), said methodcomprising administering to a subject in need of such treatment atherapeutically effective amount of a compound, or a pharmaceuticallyacceptable salt or solvate thereof, or a pharmaceutical composition asdefined herein.

In another aspect, the present invention provides a compound, or apharmaceutically acceptable salt or solvate thereof, or a pharmaceuticalcomposition as defined herein, for use in the production of an orexin-1inhibitory effect.

In another aspect, the present invention provides the use of a compound,or a pharmaceutically acceptable salt or solvate thereof, in themanufacture of a medicament for use in the production of an orexin-1inhibitory effect.

In another aspect, the present invention provides a method of producingan orexin-1 inhibitory effect in vitro, said method comprisingadministering an effective amount of a compound, or a pharmaceuticallyacceptable salt or solvate thereof.

In another aspect, the present invention provides a method of producingan orexin-1 inhibitory effect in vivo, said method comprisingadministering an effective amount of a compound, or a pharmaceuticallyacceptable salt or solvate thereof.

In another aspect, the present invention provides a method of inhibitingorexin-1 (OX₁) in vitro or in vivo, said method comprising contacting acell with an effective amount of a compound as defined herein, or apharmaceutically acceptable salt or solvate thereof.

The present invention further provides a method of synthesising acompound, or a pharmaceutically acceptable salt or solvate thereof, asdefined herein.

In another aspect, the present invention provides a compound, or apharmaceutically acceptable salt or solvate thereof, obtainable by, orobtained by, or directly obtained by a method of synthesis as definedherein.

In another aspect, the present invention provides novel intermediates asdefined herein which are suitable for use in any one of the syntheticmethods set out herein.

Preferred, suitable, and optional features of any one particular aspectof the present invention are also preferred, suitable, and optionalfeatures of any other aspect.

COMPOUNDS OF THE INVENTION

In a first aspect, the present invention provides a compound of which isselected from:

-   -   N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)-N-[(2S)-1-{[5-(trifluoro        methyl)pyrazin-2-yl]amino}propan-2-yl]pyridine-2-carboxamide;    -   N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)-N-[(2S)-1-{[5-(trifluoro        methyl)pyrimidin-2-yl]amino}propan-2-yl]pyridine-2-carboxamide;        or a pharmaceutically acceptable salt or solvate thereof.

These compounds have the general structural formula I shown below:

wherein X₁ is —CH— and X₂ is —N— or X₁ is —N— and X₂ is —CH—; or apharmaceutically acceptable salt or solvate thereof.

In an embodiment, X₁ is —CH— and X₂ is —N—, i.e. the compound is:

-   -   N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)-N-[(2S)-1-{[5-(trifluoro        methyl)pyrazin-2-yl]amino}propan-2-yl]pyridine-2-carboxamide; or        a pharmaceutically acceptable salt or solvate thereof.

In an embodiment, X₁ is —N— and X₂ is -CH-, i.e. the compound is:

-   -   N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)-N-[(2S)-1-{[5-(trifluoro        methyl)pyrimidin-2-yl]amino}propan-2-yl]pyridine-2-carboxamide;        or a pharmaceutically acceptable salt or solvate thereof.

A suitable pharmaceutically acceptable salt of a compound of theinvention is, for example, an acid-addition salt of a compound of theinvention which is sufficiently basic, for example, an acid-additionsalt with, for example, an inorganic or organic acid, for examplehydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic,formic, citric or maleic acid.

Compounds that have the same molecular formula but differ in the natureor sequence of bonding of their atoms or the arrangement of their atomsin space are termed “isomers”. Isomers that differ in the arrangement oftheir atoms in space are termed “stereoisomers”. Stereoisomers that arenot mirror images of one another are termed “diastereomers” and thosethat are non-superimposable mirror images of each other are termed“enantiomers”. When a compound has an asymmetric center, for example, itis bonded to four different groups, a pair of enantiomers is possible.An enantiomer can be characterized by the absolute configuration of itsasymmetric center and is described by the R- and S-sequencing rules ofCahn and Prelog, or by the manner in which the molecule rotates theplane of polarized light and designated as dextrorotatory orlevorotatory (i.e., as (+) or (−)-isomers respectively). A chiralcompound can exist as either individual enantiomer or as a mixturethereof. A mixture containing equal proportions of the enantiomers iscalled a “racemic mixture”.

The compounds of this invention may possess one or more asymmetriccenters; such compounds can therefore be produced as individual (R)- or(S)-stereoisomers or as mixtures thereof. Unless indicated otherwise,the description or naming of a particular compound in the specificationand claims is intended to include both individual enantiomers andmixtures, racemic or otherwise, thereof. The methods for thedetermination of stereochemistry and the separation of stereoisomers arewell-known in the art (see discussion in Chapter 4 of “Advanced OrganicChemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001),for example by synthesis from optically active starting materials or byresolution of a racemic form. It is to be understood that the presentinvention encompasses all optical, diastereoisomers and geometricisomers and mixtures thereof that possess orexin-1inhibitory activity.

The present invention also encompasses compounds of the invention asdefined herein which comprise one or more isotopic substitutions. Forexample, H may be in any isotopic form, including ¹H, ²H (D) and ³H (T);C may be in any isotopic form including ¹²C, ¹³C, and ¹⁴C; and O may bein any isotopic form, including ¹⁶O and ¹⁸O; and the like.

It is also to be understood that certain compounds of the invention mayexist in solvated as well as unsolvated forms such as, for example,hydrated forms. It is to be understood that the invention encompassesall such solvated forms that possess orexin-1 inhibitory activity.

It is also to be understood that certain compounds of the invention mayexhibit polymorphism, and that the invention encompasses all such formsthat possess orexin-1 inhibitory activity.

Compounds of the invention may exist in a number of different tautomericforms and references to compounds of the invention include all suchforms. For the avoidance of doubt, where a compound can exist in one ofseveral tautomeric forms, and only one is specifically described orshown, all others are nevertheless embraced by compounds of theinvention.

Compounds of the invention containing an amine function may also formN-oxides. A reference herein to a compound of the invention thatcontains an amine function also includes the N-oxide. Where a compoundcontains several amine functions, one or more than one nitrogen atom maybe oxidised to form an N-oxide. Particular examples of N-oxides are theN-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containingheterocycle. N-Oxides can be formed by treatment of the correspondingamine with an oxidizing agent such as hydrogen peroxide or a per-acid(e.g. a peroxycarboxylic acid), see for example Advanced OrganicChemistry, by Jerry March, 4^(th) Edition, Wiley Interscience, pages.More particularly, N-oxides can be made by the procedure of L. W. Deady(Syn. Comm. 1977, 7, 509-514) in which the amine compound is reactedwith m-chloroperoxybenzoic acid (MCPBA), for example, in an inertsolvent such as dichloromethane.

The compounds of the invention may be administered in the form of apro-drug which is broken down in the human or animal body to release acompound of the invention. A pro-drug may be used to alter the physicalproperties and/or the pharmacokinetic properties of a compound of theinvention. A pro-drug can be formed when the compound of the inventioncontains a suitable group or substituent to which a property-modifyinggroup can be attached. Examples of pro-drugs include in vivo cleavableester derivatives that may be formed at a carboxy group or a hydroxygroup in a compound of the invention and in-vivo cleavable amidederivatives that may be formed at a carboxy group or an amino group in acompound of the invention.

Accordingly, the present invention includes those compounds of theinvention as defined hereinbefore when made available by organicsynthesis and when made available within the human or animal body by wayof cleavage of a pro-drug thereof. Accordingly, the present inventionincludes those compounds of the invention that are produced by organicsynthetic means and also such compounds that are produced in the humanor animal body by way of metabolism of a precursor compound, that is acompound of the invention may be a synthetically-produced compound or ametabolically-produced compound.

A suitable pharmaceutically acceptable pro-drug of a compound of theinvention is one that is based on reasonable medical judgement as beingsuitable for administration to the human or animal body withoutundesirable pharmacological activities and without undue toxicity.

Various forms of pro-drug have been described, for example in thefollowing documents:

-   a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder,    et al. (Academic Press, 1985);-   b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985);-   c) A Textbook of Drug Design and Development, edited by    Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and    Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991);-   d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);-   e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285    (1988);-   f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984);-   g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”,    A.C.S. Symposium Series, Volume 14; and-   h) E. Roche (editor), “Bioreversible Carriers in Drug Design”,    Pergamon Press, 1987.

The in vivo effects of a compound of the invention may be exerted inpart by one or more metabolites that are formed within the human oranimal body after administration of a compound of the invention. Asstated hereinbefore, the in vivo effects of a compound of the inventionmay also be exerted by way of metabolism of a precursor compound (apro-drug).

It shall also be appreciated that compounds of the invention may also becovalently linked (at any suitable position) to other groups such as,for example, solubilising moieties (for example, PEG polymers), moietiesthat enable them to be bound to a solid support (such as, for example,biotin-containing moieties), and targeting ligands (such as antibodiesor antibody fragments).

Synthesis

In the description of the synthetic methods described below and in thereferenced synthetic methods that are used to prepare the startingmaterials, it is to be understood that all proposed reaction conditions,including choice of solvent, reaction atmosphere, reaction temperature,duration of the experiment and workup procedures, can be selected by aperson skilled in the art.

It is understood by one skilled in the art of organic synthesis that thefunctionality present on various portions of the molecule must becompatible with the reagents and reaction conditions utilised.

Necessary starting materials may be obtained by standard procedures oforganic chemistry. The preparation of such starting materials isdescribed in conjunction with the following representative processvariants and within the accompanying Examples. Alternatively, necessarystarting materials are obtainable by analogous procedures to thoseillustrated that are within the ordinary skill of an organic chemist.

It will be appreciated that during the synthesis of the compounds of theinvention in the processes defined below, or during the synthesis ofcertain starting materials, it may be desirable to protect certainsubstituent groups to prevent their undesired reaction. The skilledchemist will appreciate when such protection is required, and how suchprotecting groups may be put in place, and later removed.

For examples of protecting groups see one of the many general texts onthe subject such as ‘Protective Groups in Organic Synthesis’ by TheodoraGreen (publisher: John Wiley & Sons). Protecting groups may be removedby any convenient method described in the literature or known to theskilled chemist as appropriate for the removal of the protecting groupin question, such methods being chosen so as to effect removal of theprotecting group with the minimum disturbance of groups elsewhere in themolecule.

Thus, if reactants include, for example, groups such as amino, carboxyor hydroxy it may be desirable to protect the group in some of thereactions mentioned herein.

By way of example, a suitable protecting group for an amino oralkylamino group is, for example, an acyl group, for example an alkanoylgroup such as acetyl, an alkoxycarbonyl group, for example amethoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl group, anarylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroylgroup, for example benzoyl. The deprotection conditions for the aboveprotecting groups necessarily vary with the choice of protecting group.Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonylgroup or an aroyl group may be removed by, for example, hydrolysis witha suitable base such as an alkali metal hydroxide, for example lithiumor sodium hydroxide. Alternatively an acyl group such as atert-butoxycarbonyl group may be removed, for example, by treatment witha suitable acid as hydrochloric, sulfuric or phosphoric acid ortrifluoroacetic acid and an arylmethoxycarbonyl group such as abenzyloxycarbonyl group may be removed, for example, by hydrogenationover a catalyst such as palladium-on-carbon, or by treatment with aLewis acid for example BF₃. OEt₂. A suitable alternative protectinggroup for a primary amino group is, for example, a phthaloyl group thatmay be removed by treatment with an alkylamine, for exampledimethylaminopropylamine, or with hydrazine.

The person skilled in the art will recognise that the compounds of theinvention may be prepared, in known manner, in a variety of ways.Compounds of the invention can be prepared by the methods given below,by the methods given in the experimental or by analogous methods. Theroutes described are merely illustrative of some of the methods that canbe employed for the synthesis of compounds of the invention and theperson skilled in the art will appreciate that the order of the reactionsteps is not limited to those described. It will also be appreciatedthat the assignment of nucleophile and electrophile is not limited tothat described herein and in some cases it may be appropriate for theassignment to be reversed. Different approaches to synthetic chemistrystrategy are described in “Organic Synthesis: The DisconnectionApproach”, 2^(nd) edition, S. Warren and P. Wyatt (2008).

A compound of the invention, or a pharmaceutically-acceptable saltthereof, may be prepared by reacting an acid, or acid derivative offormula II with an amine of formula II I, wherein X₁ and X₂ are aspreviously defined in formula I (Scheme A, step i).

A suitably reactive derivative of a carboxylic acid of formula II is,for example: an acyl halide formed by the reaction of the acid and aninorganic acid chloride such as thionyl chloride; a mixed anhydride,formed by the reaction of the acid and a chloroformate such as isobutylchloroformate; an ester, formed by reaction with an alcohol in thepresence of acid or base; an activated ester, formed by the reaction ofthe acid with a phenol such as pentafluorophenyl trifluoroacetate orwith an alcohol such as N-hydroxybenzotriazole; or the product of thereaction of the acid and an amide-coupling agent such asdicyclohexylcarbodiimide. Where a carboxylic acid of formula II isconverted to an ester, for example by the reaction of an acyl chloridewith an organic alcohol, such as methanol, this may be reacted with anamine of formula III in the presence of an organometallic activatingagent, for example a Grignard reagent such as isopropylmagnesiumbromide. Typically, a carboxylic acid of formula II and an amine offormula III, in a suitable solvent, such as DMF in the presence of anon-nucleophilic base, such as DIPEA, are treated with an amide-couplingagent, such as HATU.

Compounds of formula II may be commercially available or prepared bytechniques known, or apparent to, those skilled in the art. Compounds offormula II may be prepared by: acid or base catalysed hydrolysis of anester, an amide or a nitrile, such as the hydrolysis of a methyl esterwith sodium hydroxide; transition metal catalysed oxidation of analdehyde or alcohol; treatment of an organolithium or Grignard reagentwith carbon dioxide; transition metal catalysed carbonylation of an arylhalide in the presence of water. Transition metal catalysedcarbonylation of an aryl halide in the presence of an amine of formulaIII may form a compound of formula I directly.

It will be appreciated by those skilled in the art that compounds offormula I and formula III, wherein X₁ and X₂ are as previously definedin formula I, may be prepared by incorporating suitable protecting groupand route selection strategies into the general synthetic chemistrymethodology described in Scheme B, wherein X₁ and X₂ are as previouslydefined in formula I and Y is either: H;

or an amine protecting group such as benzyl, 3,4-dimethoxybenzylp-methoxybenzyl, carbobenzyloxy, tert-butyloxycarbonyl,9-fluorenylmethyloxycarbonyl, acetyl, benzoyl, p-methoxyphenyl, tosyl,nosyl or trifluoroacetyl.

A compound of formula IV, or a pharmaceutically-acceptable salt thereof,wherein X₁ and X₂ are as previously defined in formula I, may beprepared by reacting an amine of formula V with a compound of formulaZAr, wherein Ar is

and X₁ and X₂ are as previously defined in formula I, and Z is asubstituent amenable to transition-metal catalysed amination chemistry(Scheme B, step ii). A compound of formula ZAr, wherein Z is a halidesuch as bromide or chloride, a boronic acid or boronate ester, or anactivated alcohol such as a triflate, may be converted to a compound offormula IV by reaction with an amine of formula V in the presence of atransition metal catalyst such as[1,1′-bis(diphenylphosphio)ferrocene]-dichloropalladium(II) or Pd₂(dba)₃in the presence of a base such as potassium carbonate or sodiumtert-butoxide and a suitable ligand such as triphenylphosphine or4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene. Typically the reactionis carried out in toluene, at relux, using Pd₂(dba)₃ as a catalyst inthe presence of BINAP and sodium tert-butoxide.

Alternatively, a compound of formula IV may be prepared by reacting anamine of formula V with a compound of formula ZAr, wherein Ar is

and X₁ and X₂ are as previously defined in formula I, and Z is a leavinggroup such as a halide, for example iodide or bromide, or an activatedalcohol, for example tosylate or mesylate, in the presence of anon-nucleophilic base such as DBU, sodium tert-butoxide, potassiumcarbonate, a tertiary amine for example DIPEA, or a heterocyclic basefor example pyridine (Scheme B, step ii). Typically the reaction iscarried out using DIPEA, as a base, in NMP at 130° C.

A compound of formula IV, or a pharmaceutically-acceptable salt thereof,wherein X₁ and X₂ are as previously defined in formula I, may beprepared by reacting an amine of formula H₂NAr, wherein Ar is

and X₁ and X₂ are as previously defined in formula I, with an aldehydeof formula VI (Scheme B, step iii). A compound of formula IV may beprepared by reductive amination of compounds of formula VI with an amineof formula H₂NAr in the presence of a suitable reducing agent such assodium cyanoborohydride, NaBH(OAc)₃ or sodium borohydride, in a polarsolvent such as methanol, ethanol, THF, DCE or DCM either alone or incombination with an acid such as AcOH. Typically the reaction is carriedout using NaBH(OAc)₃ in DCE at ambient temperature.

An amine of formula V may be prepared by reductive amination aspreviously described for Scheme B step iii, between an aldehyde offormula VI and an amine, amine equivalent or suitably protected amine(Scheme B, step iv).

The person skilled in the art will recognise that aldehydes of formulaVI can be prepared in a variety of ways. Typically aldehydes of formulaVI are prepared by the oxidation of an alcohol of formula VII in DCMusing Dess-Martin's Periodinane and NaHCO₃ (Scheme B, step v).

Compounds of formula V may also be prepared by reduction of an amide offormula VIII with a hydride reagent such as LiAlH₄ or by catalytichydrogenation (Scheme B, step vi). Typically the reaction is carried outin THF or diethyl ether using LiAIH₄ at 0° C. The person skilled in theart will recognise that the preparation of amines of formula V is notlimited to the methods described herein and can be achieved in knownmanner, in a variety of ways.

The person skilled in the art will recognise that alcohols of formulaVII can be prepared in a variety of known ways. For example, alcohols offormula VII may be prepared by reduction of carbonyl containingcompounds such as aldehydes, carboxylic acids or carboxylic acidequivalents, such as a carboxylic esters, of formula IX (Scheme B, stepvii) with a suitable reducing agent such as sodium borohydride, LiAlH₄,diisobutyl aluminium hydride or LiBH₄. Typically alcohols of formula VIIare prepared by reduction of carboxylic ester equivalents of carboxylicacids of formula IX using LiBH₄ in THF at ambient temperature. It willbe appreciated by a person skilled in the art that a carboxylic esterequivalent of a carboxylic acid of formula IX can be prepared in avariety of known ways.

Compounds of formula IX may be prepared from a suitablyprotected/activated derivative of an amino acid of formula X (Scheme B,step ix). It will be appreciated by those skilled in the art thatconversion of an amino acid of formula X to a compound of formula IX viaa synthetic strategy of protection/activation may require multiplereaction steps, and can be achieved in a variety of ways of knownmanner. For example, compounds of formula IX can be prepared by:conversion of an amino acid of formula X to an activated amide such as atrifluoroacetamide by reaction with trifluoracetic anhydride, followedby deprotonation with a base such as sodium hydride, alkylation with analkyl halide of formula CH₃Z, wherein Z is a leaving group such as ahalide or an activated alcohol, for example methyl iodide, andhydrolysis with a suitable base such as sodium hydroxide; benzylicprotection by reaction of an amino acid of formula X with a suitablealdehyde or aldehyde equivalent such as benzaldehyde, followed byreductive amination with an suitable aldehyde or aldehyde equivalent,such as formaldehyde or paraformaldehyde, followed by catalytichydrogenation with a transition metal catalyst such as palladium underan atmosphere of hydrogen; conversion of an amino acid of formula X to acarbamate by reaction with an anhydride or acid chloride such as withdi-tert-butyl dicarbonate, followed by reduction with a metal-hydridesuch as LiAlH₄.

Natural and non-natural amino acids of formula X and their derivativesare either commercially available or may be prepared by methods known tothose skilled in the art. For reviews of the synthesis of amino acids,see (a) C. Najera and J. M. Sansano, Chem. Rev., 2007, 107, 4584; (b) R.M. Williams and J. A. Hendrix, Chem. Rev., 1992, 92, 889; (c) R. O.Duthaler, Tetrahedron, 1994, 50, 1539.

Pharmaceutical Compositions

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of the inventionas defined hereinbefore, or a pharmaceutically acceptable salt orsolvate thereof, in association with a pharmaceutically acceptablediluent or carrier.

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, intramuscular,intraperitoneal or intramuscular dosing or as a suppository for rectaldosing).

The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents.

An effective amount of a compound of the present invention for use intherapy of proliferative disease is an amount sufficient tosymptomatically relieve in a warm-blooded animal, particularly a humanthe symptoms of infection, to slow the progression of infection, or toreduce in patients with symptoms of infection the risk of getting worse.

The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, forexample from 1 to 30 mg) compounded with an appropriate and convenientamount of excipients which may vary from about 5 to about 98 percent byweight of the total composition.

The size of the dose for therapeutic or prophylactic purposes of acompound of the formula I will naturally vary according to the natureand severity of the conditions, the age and sex of the animal or patientand the route of administration, according to well-known principles ofmedicine.

In using a compound of the invention for therapeutic or prophylacticpurposes it will generally be administered so that a daily dose in therange, for example, 0.1 mg/kg to 75 mg/kg body weight is received, givenif required in divided doses. In general lower doses will beadministered when a parenteral route is employed. Thus, for example, forintravenous or intraperitoneal administration, a dose in the range, forexample, 0.1 mg/kg to 30 mg/kg body weight will generally be used.Similarly, for administration by inhalation, a dose in the range, forexample, 0.05 mg/kg to 25 mg/kg body weight will be used. Oraladministration may also be suitable, particularly in tablet form.Typically, unit dosage forms will contain about 0.5 mg to 0.5 g of acompound of this invention.

Therapeutic Uses and Applications

The compounds of the invention are selective inhibitors of orexin-1activity. As a consequence, they are potentially useful therapeuticagents for the treatment of diseases or conditions in which orexin-1receptor activity is implicated.

Thus, in one aspect, the present invention relates to a compound of theinvention as defined herein, or a pharmaceutically acceptable salt orsolvate thereof, or a pharmaceutical composition as defined herein, foruse in therapy.

In another aspect, the present invention relates to a compound of theinvention as defined herein, or a pharmaceutically acceptable salt orsolvate thereof, or a pharmaceutical composition as defined herein, foruse in the treatment of diseases or conditions in which orexin-1 (OX₁)activity is implicated.

In another aspect, the present invention relates to the use of acompound of the invention as defined herein, or a pharmaceuticallyacceptable salt or solvate thereof, in the manufacture of a medicamentfor use in the treatment of diseases or conditions in which orexin-1(OX₁) activity is implicated.

In another aspect, the present invention relates to a method of treatinga disease or condition in which orexin-1 (OX₁) activity is implicated,said method comprising administering to a subject in need of suchtreatment a therapeutically effective amount of a compound of theinvention as defined herein, or a pharmaceutically acceptable salt orsolvate thereof, or a pharmaceutical composition as defined herein.

Examples of particular diseases or conditions that the compounds offormula (I) and their pharmaceutically acceptable salts may be used totreat include, but are not limited to, any one of the following:schizophrenia and other psychotic disorders (e.g., psychotic disorder,psychosis or schizoaffective disorder); dementia and other cognitivedisorders; anxiety disorders (e.g., generalized anxiety disorder,post-traumatic stress disorder, panic disorders, acute stress disorder,social anxiety disorder, phobias including agoraphobia, obsessivecompulsive disorder, trichlofiilomania or body dismorphic disorder);mood disorders (e.g., depressive disorders, major depressive disorders,bipolar disorders including bipolar I and II, bipolar mania, bipolardepression); addiction including substance dependence (e.g. cocaine,opiates, cannabis or prescription drug dependence), alcohol dependence,nicotine dependence or gambling disorder; eating disorders (e.g. bingeeating, bulimia nervosa, anorexia nervosa or obesity); sleep disorders(e.g. rapid eye movement sleep disorder); disorders usually firstdiagnosed in infancy, childhood, or adolescence (e.g., attention-deficitdisorder, autistic spectrum disorders, Rett syndrome, Fragile Xsyndrome, Asperger syndrome and disruptive behaviour disorders);restless leg syndrome; pain (e.g. neuropathic pain includingchemotherapy induced pain or migraine); osteoporosis andneurodegenerative disorders (e.g. Parkinson's or Alzheimer's disease).

In particular, the compounds of the invention (includingpharmaceutically acceptable salts) may be used in the treatment of thepositive symptoms of schizophrenia, schizophreniform disorder orschizoaffective disorder (e.g. voices or hallucinations), cognitivedisorders (such as dementia and impaired learning), anxiety disorders(such as post-traumatic stress disorder or panic disorders), oraddiction.

The invention also provides a compound of formula I as defined hereinfor use in the treatment of at least one symptom or condition associatedwith the treatment of any one of the following: schizophrenia and otherpsychotic disorders (e.g., psychotic disorder, psychosis orschizoaffective disorder); dementia and other cognitive disorders;anxiety disorders (e.g., generalized anxiety disorder, post-traumaticstress disorder, panic disorders, acute stress disorder, social anxietydisorder, phobias including agoraphobia, obsessive compulsive disorder,trichotillomania or body dysmorphic disorder); mood disorders (e.g.,depressive disorders, major depressive disorders, bipolar disordersincluding bipolar I and II, bipolar mania, bipolar depression);addiction including substance dependence (e.g. cocaine, opiates,cannabis or prescription drug dependence), alcohol dependence, nicotinedependence or gambling disorder; eating disorders (e.g. binge eating,bulimia nervosa, anorexia nervosa or obesity); sleep disorders (e.g.rapid eye movement sleep disorder); disorders usually first diagnosed ininfancy, childhood, or adolescence (e.g., attention-deficit disorder,autistic spectrum disorders, Rett syndrome, Fragile X syndrome, Aspergersyndrome and disruptive behaviour disorders); restless leg syndrome;pain (e.g. neuropathic pain including chemotherapy induced pain ormigraine); osteoporosis and neurodegenerative disorders (e.g.Parkinson's or Alzheimer's disease) which comprises administering to apatient in need thereof a therapeutically effective amount of a compoundof formula (I) or a pharmaceutically acceptable salt thereof ashereinbefore defined.

Such symptoms and conditions include, but are not limited to, anxiety,agitation, hostility, panic, an eating disorder, an affective symptom, amood symptom, a negative and positive psychotic symptom commonlyassociated with psychosis and neurodegenerative disorder.

Further particular examples of conditions in which orexin-1 (OX₁)activity is implicated include behavioural arousal, eating disorders(e.g. binge eating, obesity), psychiatric conditions (e.g.schizophrenia, anxiety, mood disorders, reward seeking behaviours,alcohol or drug (e.g. nicotine) addiction, panic disorders (such aspanic attacks) and/or anxiety).

In another aspect, the present invention provides a compound, or apharmaceutically acceptable salt or solvate thereof, or a pharmaceuticalcomposition as defined herein, for use in the treatment of schizophreniaand other psychotic disorders (e.g., psychotic disorder, psychosis orschizoaffective disorder); dementia and other cognitive disorders;anxiety disorders (e.g., generalized anxiety disorder, post-traumaticstress disorder, panic disorders, acute stress disorder, social anxietydisorder, phobias including agoraphobia, obsessive compulsive disorder,trichotillomania or body dysmorphic disorder); mood disorders (e.g.,depressive disorders, major depressive disorders, bipolar disordersincluding bipolar I and II, bipolar mania, bipolar depression);addiction including substance dependence (e.g. cocaine, opiates,cannabis or prescription drug dependence), alcohol dependence, nicotinedependence or gambling disorder; eating disorders (e.g. binge eating,bulimia nervosa, anorexia nervosa or obesity); sleep disorders (e.g.rapid eye movement sleep disorder); disorders usually first diagnosed ininfancy, childhood, or adolescence (e.g., attention-deficit disorder,autistic spectrum disorders, Rett syndrome, Fragile X syndrome, Aspergersyndrome and disruptive behaviour disorders); restless leg syndrome;pain (e.g. neuropathic pain including chemotherapy induced pain ormigraine); osteoporosis and neurodegenerative disorders (e.g.Parkinson's or Alzheimer's disease).

In another aspect, the present invention provides a compound, or apharmaceutically acceptable salt or solvate thereof, or a pharmaceuticalcomposition as defined herein, for use in the treatment of behaviouralarousal, eating disorders (e.g. binge eating, obesity), psychiatricconditions (e.g. schizophrenia, anxiety, mood disorders, reward seekingbehaviours, alcohol or drug (e.g. nicotine) addiction, panic disporders(such as panic attacks) and/or anxiety).

In another aspect, the present invention provides the use of a compound,or a pharmaceutically acceptable salt or solvate thereof, in themanufacture of a medicament for use in the treatment of schizophreniaand other psychotic disorders (e.g., psychotic disorder, psychosis orschizoaffective disorder); dementia and other cognitive disorders;anxiety disorders (e.g., generalized anxiety disorder, post-traumaticstress disorder, panic disorders, acute stress disorder, social anxietydisorder, phobias including agoraphobia, obsessive compulsive disorder,trichotillomania or body dysmorphic disorder); mood disorders (e.g.,depressive disorders, major depressive disorders, bipolar disordersincluding bipolar I and II, bipolar mania, bipolar depression);addiction including substance dependence (e.g. cocaine, opiates,cannabis or prescription drug dependence), alcohol dependence, nicotinedependence or gambling disorder; eating disorders (e.g. binge eating,bulimia nervosa, anorexia nervosa or obesity); sleep disorders (e.g.rapid eye movement sleep disorder); disorders usually first diagnosed ininfancy, childhood, or adolescence (e.g., attention-deficit disorder,autistic spectrum disorders, Rett syndrome, Fragile X syndrome, Aspergersyndrome and disruptive behaviour disorders); restless leg syndrome;pain (e.g. neuropathic pain including chemotherapy induced pain ormigraine); osteoporosis and neurodegenerative disorders (e.g.Parkinson's or Alzheimer's disease).

In another aspect, the present invention provides the use of a compound,or a pharmaceutically acceptable salt or solvate thereof, in themanufacture of a medicament for use in the treatment of behaviouralarousal, eating disorders (e.g. binge eating, obesity), psychiatricconditions (e.g. schizophrenia, anxiety, mood disorders, reward seekingbehaviours, alcohol or drug (e.g. nicotine) addiction, panic disorders(such as panic attacks) and/or anxiety).

In another aspect, the present invention provides a method of treatingschizophrenia and other psychotic disorders (e.g., psychotic disorder,psychosis or schizoaffective disorder); dementia and other cognitivedisorders; anxiety disorders (e.g., generalized anxiety disorder,post-traumatic stress disorder, panic disorders, acute stress disorder,social anxiety disorder, phobias including agoraphobia, obsessivecompulsive disorder, trichotillomania or body dysmorphic disorder); mooddisorders (e.g., depressive disorders, major depressive disorders,bipolar disorders including bipolar I and II, bipolar mania, bipolardepression); addiction including substance dependence (e.g. cocaine,opiates, cannabis or prescription drug dependence), alcohol dependence,nicotine dependence or gambling disorder; eating disorders (e.g. bingeeating, bulimia nervosa, anorexia nervosa or obesity); sleep disorders(e.g. rapid eye movement sleep disorder); disorders usually firstdiagnosed in infancy, childhood, or adolescence (e.g., attention-deficitdisorder, autistic spectrum disorders, Rett syndrome, Fragile Xsyndrome, Asperger syndrome and disruptive behaviour disorders);restless leg syndrome; pain (e.g. neuropathic pain includingchemotherapy induced pain or migraine); osteoporosis andneurodegenerative disorders (e.g. Parkinson's or Alzheimer's disease),said method comprising administering to a subject in need of suchtreatment a therapeutically effective amount of a compound, or apharmaceutically acceptable salt or solvate thereof, or a pharmaceuticalcomposition as defined herein.

In another aspect, the present invention provides a method of treatingbehavioural arousal, eating disorders (e.g. binge eating, obesity),psychiatric conditions (e.g. schizophrenia, anxiety, mood disorders,reward seeking behaviours, alcohol or drug (e.g. nicotine) addiction,panic disorders (such as panic attacks) and/or anxiety), said methodcomprising administering to a subject in need of such treatment atherapeutically effective amount of a compound, or a pharmaceuticallyacceptable salt or solvate thereof, or a pharmaceutical composition asdefined herein.

In another aspect, the present invention provides a compound, or apharmaceutically acceptable salt or solvate thereof, or a pharmaceuticalcomposition as defined herein, for use in the production of an orexin-1inhibitory effect.

In another aspect, the present invention provides the use of a compound,or a pharmaceutically acceptable salt or solvate thereof, in themanufacture of a medicament for use in the production of an orexin-1inhibitory effect.

In another aspect, the present invention provides a method of producingan orexin-1 inhibitory effect in vitro, said method comprisingadministering an effective amount of a compound, or a pharmaceuticallyacceptable salt or solvate thereof.

In another aspect, the present invention provides a method of producingan orexin-1 inhibitory effect in vivo, said method comprisingadministering an effective amount of a compound, or a pharmaceuticallyacceptable salt or solvate thereof.

In another aspect, the present invention provides a method of inhibitingorexin-1 (OX₁) in vitro and/or in vivo, said method comprisingcontacting a cell with an effective amount of a compound as definedherein, or a pharmaceutically acceptable salt or solvate thereof.

Routes of Administration

The compounds of the invention or pharmaceutical composition comprisingthe active compound may be administered to a subject by any convenientroute of administration, whether systemically/ peripherally or topically(i.e. at the site of desired action).

Routes of administration include, but are not limited to, oral (e.g., byingestion); buccal; sublingual; transdermal (including, e.g., by apatch, plaster, etc.); transmucosal (including, e.g., by a patch,plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., byeyedrops); pulmonary (e.g., by inhalation or insufflation therapy using,e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., bysuppository or enema); vaginal (e.g., by pessary); parenteral, forexample, by injection, including subcutaneous, intradermal,intramuscular, intravenous, intraarterial, intracardiac, intrathecal,intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal,intratracheal, subcuticular, intraarticular, subarachnoid, andintrasternal; by implant of a depot or reservoir, for example,subcutaneously or intramuscularly.

Combination Therapies

The compounds of the invention may be administered alone as amonotherapy or may administered in combination with one or moreadditional therapeutic agents. The selection of the one or moreadditional therapeutic agents will of course vary depending on thedisease or condition to be treated and its severity.

It is commonplace to use combination therapies to treat certain medicalconditions.

Therefore, the treatment defined hereinbefore may be applied as a soletherapy or may involve, in addition to the compound of the invention,treatment with one or more additional therapeutic agents.

Such conjoint/combination treatment may be achieved by way of thesimultaneous, sequential or separate dosing of the individual componentsof the treatment. Such combination products employ the compounds of thisinvention within the dosage range described hereinbefore and the otherpharmaceutically-active agent within its approved dosage range.

According to a particular aspect of the invention there is provided acombination suitable for use in the treatment of a disease or conditionin which orexin-1 receptor activity is implicated, comprising a compoundof the invention as defined hereinbefore, or a pharmaceuticallyacceptable salt or solvate thereof, and another therapeutic agent.

According to this aspect of the invention there is provided acombination suitable for use in the treatment of behavioural arousal,eating disorders (e.g. binge eating, obesity), psychiatric conditions(e.g. schizophrenia, anxiety, mood disorders, reward seeking behaviours,alcohol or drug (e.g. nicotine) addiction and/or anxiety), thecombination comprising a compound of the invention as definedhereinbefore, or a pharmaceutically acceptable salt or solvate thereof,and one or more additional therapeutic agents.

In a further aspect of the invention there is provided a compound of theinvention or a pharmaceutically acceptable salt or solvate thereof, incombination with one or more additional therapeutic agents.

Herein, where the term “combination” is used it is to be understood thatthis refers to simultaneous, separate or sequential administration. Inone aspect of the invention “combination” refers to simultaneousadministration. In another aspect of the invention “combination” refersto separate administration. In a further aspect of the invention“combination” refers to sequential administration. Where theadministration is sequential or separate, the delay in administering thesecond component should not be such as to lose the beneficial effect ofthe combination.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of the invention,or a pharmaceutically acceptable salt or solvate thereof in combinationwith one or more additional therapeutic agents in association with apharmaceutically acceptable diluent or carrier.

According to a particular aspect of the invention there is provided acombination suitable for use in the treatment of schizophrenia and otherpsychotic disorders (e.g., psychotic disorder, psychosis orschizoaffective disorder); dementia and other cognitive disorders;anxiety disorders (e.g., generalized anxiety disorder, post-traumaticstress disorder, panic disorders, acute stress disorder, social anxietydisorder, phobias including agoraphobia, obsessive compulsive disorder,trichotillomania or body dysmorphic disorder); mood disorders (e.g.,depressive disorders, major depressive disorders, bipolar disordersincluding bipolar I and II, bipolar mania, bipolar depression);addiction including substance dependence (e.g., cocaine, opiates,cannabis or prescription drug dependence), alcohol dependence, nicotinedependence or gambling disorder; eating disorders (e.g., binge eating,bulimia nervosa, anorexia nervosa or obesity); sleep disorders (e.g.,rapid eye movement sleep disorder); disorders usually first diagnosed ininfancy, childhood, or adolescence (e.g., attention-deficit disorder,autistic spectrum disorders, Rett syndrome, Fragile X syndrome, Aspergersyndrome and disruptive behaviour disorders); restless leg syndrome;pain (e.g. neuropathic pain including chemotherapy induced pain ormigraine); osteoporosis and neurodegenerative disorders (e.g.Parkinson's or Alzheimer's disease), the combination comprising acompound of the invention as defined hereinbefore, or a pharmaceuticallyacceptable salt or solvate thereof, and another therapeutic agent.

According to a particular aspect of the invention there is provided acombination suitable for use in the treatment of behavioural arousal,eating disorders (e.g., binge eating, obesity), psychiatric conditions(e.g,. schizophrenia, anxiety, mood disorders, reward seekingbehaviours, alcohol or drug (e.g., nicotine) addiction, panic disorders(such as panic attacks) and/or anxiety) comprising a compound of theinvention as defined hereinbefore, or a pharmaceutically acceptable saltor solvate thereof, and another therapeutic agent.

Examples of other therapeutic agents that may be used as part of acombination therapy with a compound of the present invention (e.g., asone of two or more active agents as part of double or triplecombinations) include, but are not limited to, the following:

-   (i) antidepressants such as, for example, amitriptyline, amoxapine,    bupropion, citalopram, clomipramine, desipramine, doxepin    duloxetine, elzasonan, escitaiopram, fluvoxamine, fluoxetine,    gepirone, imipramine, ipsapirone, maprotiline, nortriptyline,    nefazodone, paroxetine, phenelzine, protriptyline, reboxetine,    robaizotan, sertraline, sibutramine, tianeptine, thionisoxetine,    tranylcypromaine, trazodone, trimipramine, venlafaxine, vortioxetine    and equivalents and pharmaceutically active isomer(s) and/or    metaboiite(s) thereof;-   (ii) antipsychotics including, for example, amisulpride,    aripiprazole, asenapine, benzisoxidil, bifeprunox, brexpiprazole,    carbamazepine, cariprazine, clozapine, chlorpromazine, debenzapine,    divalproex, duloxetine, eszopiclone, haloperidol, iloperidone,    lamotrigine, loxapine, iurasidone, mesoridazine, olanzapine,    paliperidone, perlapine, perphenazine, phenothiazine,    phenyibutlypiperidine, pimozide, prochlorperazine, quetiapine,    risperidone, sertindole, sulpiride, suproclone, suri clone,    thioridazine, trifluoperazine, trimetozine, valproate, valproic    acid, zopiclone, zotepine, zicronapine, ziprasidone, and equivalents    and pharmaceutically active isomer(s) and/or metabolite(s) thereof;-   (iii) anxiolytics including, for example, alnespirone, azapirones,    benzodiazepines, barbiturates, and equivalents and pharmaceutically    active isomer(s) and/or metabolite(s) thereof. Example anxiolytics    include adinazolam, alprazolam, balezepam, bentazepam, bromazepam,    brotizolam, buspirone, clonazepam, clorazepate, chlordiazepoxide,    cyprazeparn, diazepam, diphenhydramine, estazolam, fenobam,    flunitrazepam, flurazepam, fosazepam, lorazepam, lormetazepam,    meprobamate, midazolam, nitrazepam, oxazepam, prazepam, quazepam,    reclazepam, tracazolate, trepipam, temazepam, triazolam, uidazepam,    and zolazepam; and equivalents and pharmaceutically active isomer(s)    and/or metabolite(s) thereof;-   (iv) anticonvulsants including, for example, carbamazepine,    valproate, lamotrigine, evetiracetam and gabapentin, and equivalents    and pharmaceutically active isomer(s) and/or metabolite(s) thereof;-   (v) Alzheimer's therapies including, for example, donepezil,    gaiantamine, memantine, rivastigmine, tacrine, and equivalents and    pharmaceutically active isomer(s) and/or metabolite(s) thereof;-   (vi) Parkinson's therapies including, for example, L-dopa,    ropinirole, pramipexoie, monoamine oxidase type B (MAO-B) inhibitors    such as deprenyi, selegiline and rasagiiine, catechol —O-methyS    transferase (COMT) inhibitors such as entacapone or tolcapone,    adenosine A-2 inhibitors, dopamine re-uptake inhibitors, NMDA    antagonists, Nicotine agonists, and Dopamine agonists and inhibitors    of neuronal nitric oxide synthase, and equivalents and    pharmaceutically active isomer(s) and/or metabolite(s) thereof;-   (vii) migraine therapies including, for example, aimotriptan,    amantadine, botulinum toxin A, bromocriptine, butalbital,    cabergoiine, dichloraiphenazone, dihydroergotamine, eietriptan,    frovatriptan, lisuride, naratriptan, pergolide, pramipexoie,    rizatriptan, ropinirole, sumatriptan, topiramate, zolmitriptan, and    zomitriptan, and equivalents and pharmaceutically active isomer(s)    and/or metabolite(s) thereof;-   (viii) stroke therapies including, for example, abciximab, activase,    citicoline, desmoteplase, and equivalents and pharmaceutically    active isomer(s) and/or metabolite(s) thereof;-   (ix) urinary incontinence therapies including, for example,    darafenacin, duloxetine, falvoxate, mirabegron, oxybutynin,    propiverine, robalzotan, solifenacin, and tolterodine, and    equivalents and pharmaceutically active isomer(s) and/or    metabolite(s) thereof;-   (x) neuropathic pain therapies including, for example, capsaicin,    gabapentin, iidoderm, and pregabalin, and equivalents and    pharmaceutically active isomer(s) and/or metabolite(s) thereof;-   (xi) nociceptive pain therapies such as, for example, celecoxib,    etoricoxib, lumiracoxib, rofecoxib, valdecoxib, diclofenac,    loxoprofen, naproxen, and paracetamol, and equivalents and    pharmaceutically active isomer(s) and/or metaboiite(s) thereof;-   (xii) insomnia therapies including, for example, allobarbital,    aionimid, amobarbital, benzoctamine, butabarbital, capuride,    chloral, cloperidone, clorethate, dexclamol, ethchlorvynol,    eszopiclone, etomidate, glutethimide, halazepam, hydroxyzine,    iorediplon, mecloqualone, melatonin, mephobarbital, methaqualone,    midaflur, nisobamate, pentobarbital, phenobarbital, propofol,    ralmeteon, roletamide, suvorexant, triclofos, secobarbital,    zaleplon, and Zolpidem, zopiclone and equivalents and    pharmaceutically active isomer(s) and/or metabolite(s) thereof;-   (xiii) mood stabilizers including, for example, carbamazepine,    divalproex, gabapentin, lamotrigine, lithium, olanzapine,    quetiapine, valproate, valproic acid, and verapamil, and equivalents    and pharmaceutically active isomer(s) and/or metabolite(s) thereof;-   (xiv) 5HT1B ligands such as, for example, compounds disclosed in WO    99/05134 and WO 02/08212;-   (xv) mGluR2 agonists;-   (xvi) alpha 7 nicotinic agonists such as, for example, compounds    disclosed in WO 96/006098, WO 97/030998, WO 99/003859, WO 00/042044,    WO 01/029034, WO 01/60821, WO 01/36417, WO 02/096912, WO 03/087102,    WO 03/087103, WO 03/087104, WO 2004/016617, WO 2004/016616, and WO    2004/019947;(xvii) chemokine receptor CCR1 inhibitors;-   (xviii) delta opioid agonists such as, for example, compounds    disclosed in WO 97/23466 and WO 02/094794; and-   (xviv) osteoporosis therapies such as, for example, bisphosphonates,    denosumab, raloxifene, calcitonin, strontium ranelate, HRT, calcium    and vitamin D.-   (xvv) other agents useful in the treatment of addictive disorders    such as buprenorphine, naloxone, metyrapone, naltrexone, nalmefene,    ketoconazole, mirtazapine, atomoxetine, gabapentin, muscimol,    baclofen, progabide, pregabalin, riluzole, vigabatrin, valproic    acid, tiagabine, lamotrigine, phenytoin, carbamazepine, topiramate,    a barbiturate, carisoprodol, chloral hydrate, glutethimide,    L-theanine, kava, methaqualone, neuroactive steroids, z-drugs,    propofol, scullcap, valerian, gamma-butyrolactone,    gamma-hydroxybutyric acid, phenibut, deramciclane, hyperforin,    gabaculine, phenelzine, valproate, vigabatrin, lemon balm (Melissa    officinalis), GABA, L-glutamine, picamilon, and tetanospasmin.

Such combination therapies employ the compounds of this invention withinthe dosage range described herein and the other pharmaceutically activeagent within approved dosage ranges and/or the dosage such as describedin the publication reference.

EXAMPLES Synthesis of Compounds General Procedures:

Methods for preparing the compounds of this invention are illustrated inthe following Examples. Starting materials are made according toprocedures known in the art or as illustrated herein, or are availablecommercially. Commercial reagents were used without furtherpurification. Where no reaction temperature is included, the reactionwas performed at ambient temperature which is typically 18-27° C.

Where compounds described in the invention are characterized by ¹H NMRspectroscopy, spectra were recorded on 500 MHz Bruker, 400 MHz Bruker or400MHz JEOL instruments. Where no temperature is included the spectrawere recorded at ambient temperature. Chemical shift values areexpressed in parts per million (ppm). Where NMR spectra are complex dueto the presence of interconverting isomers, approximate partialintegrations of signals are reported. The following abbreviations areused for the multiplicity of the NMR signals: s=singlet, b=broad,t=triplet, q=quartet, m=multiplet, d=doublet.

Where compounds described in the invention are characterized by LCMSdata, retention time and molecular weight are determined using theconditions listed below. In cases where compounds of the inventionappear as slowly interconverting stereoisomers, multiple retention timesare reported.

Method A: Agilent 1260 LC with MS detection (API electrospray). Column:Agilent Poroshell 120 EC-C18 (2.7 μm, 3.0×50 mm) Conditions: Water+0.1%formic acid [eluent A]; MeCN [eluent B]. Gradient: 5 to 95 to 5% B over3.5 min.

Method B: Waters ZQ MS with Agilent 1100 HPLC at 210-420 nm (ESI).Column: Phenomenex Gemini13 NXC18 (3 μm, 2.0×50 mm). Conditions: 2 mMammonium bicarbonate, buffered to pH10 [Eluent A]; MeCN [Eluent B].Gradient: 1 to 100 to 1% B over 3.5 min.

Method C: Waters ZQ MS with Agilent 1100 HPLC at 210-420 nm (ESI).Column: Phenomenex Gemini—NXC18 (3 μm, 2.0×100 mm). Conditions: 2 mMammonium bicarbonate, buffered to pH10 [Eluent A]; MeCN [Eluent B].Gradient: 5 to 100 to 5% B over 7 min.

ABBREVIATIONS

-   DCE Dichloroethane-   DCM Dichloromethane-   DEAD Diethyl azodicarboxylate-   DIPEA N,N-Diisopropylethylamine-   DMF N,N-Dimethylformamide-   DMSO Dimethylsulfoxide-   EtOAc Ethylacetate-   HATU    N-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium    hexafluorophosphate N-oxide-   HBTU N,N,N′N′-Tetramethyl-O-(1H-benzotriazol-1-yl)uranium    hexafluorophosphate-   HCl Hydrogen chloride-   HPLC High Performance Liquid Chromatography-   hr(s) hour(s)-   IPA Isopropyl alcohol-   LCMS Liquid Chromatography Mass Spectrometry-   LiAlH₄ Lithium aluminium hydride-   LiOH Lithium hydroxide-   MeCN Acetonitrile-   MgSO₄ Magnesium sulfate-   min(s) minute(s)-   NaBH(OAc)₃ Sodium triacetoxyborohydride-   NaHCO₃ Sodium bicarbonate-   Na₂SO₄ Sodium sulfate-   NMP N-Methylpyrollidinone-   NMR Nuclear magnetic resonance-   tBME tert-Butyl methyl ether-   THF Tetrahydrofuran-   TFA Trifluoroacetic acid

Preparation of 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid lithiumsalt (1:1) (Int 4, Scheme 1)

Preparation of 2-methyl-5-(2H-1,2,3-triazol-2-yl)pyridine (Int 1)

5-Bromo-2-methylpyridine (124 g, 720 mmol), 1H-1,2,3-triazole (210 mL,3600 mmol), Rac-trans-N,N′-dimethylcyclohexane-1 ,2-diamine (26.0 g, 183mmol), copper powder (46 g, 720 mmol) and potassium carbonate (200 g,720 mmol) were combined in NMP (250 mL). The mixture was heated to 120°C. and stirred for 4 hrs. The mixture was allowed to cool to 50-90° C.and diluted with water (600 mL). The mixture was then added to anagitated mixture of water (1900 mL) and concentrated ammonia solution(124 mL). tBME (600 mL) was added and the mixture was stirred for 0.5hrs and then filtered washing with tBME (300 mL). The biphasic filtratewas separated. The aqueous was extracted with tBME (2×500 mL) and theorganics combined and used directly in the next step.

LCMS (Method A): 1.67 min, 161 [M+H]+

Preparation of 2-methyl-5-(2H-1,2,3-triazol-2-yl)pyridine 1-oxide (Int2)

To the Int 1 tBME solution was added 3-chloroperbenzoic acid (77%, 156g, 670 mmol) and the mixture was stirred overnight at ambienttemperature. The mixture was then heated to 45-50° C. Triethylamine (4mL) was added and the mixture stirred for 15 mins. The mixture was thensubjected to azeotropic drying with additions of tBME. The mixture wasthen cooled to 10-20° C. and the crude solid product was filtered,washed with tBME (300 mL) and dried. The crude product was stirred inIPA (680 mL) and heated to reflux to cause dissolution. The mixture wasthen allowed to cool to ambient temperature and stirred overnight. Themixture was then cooled to approximately 5° C. and stirred for 0.5 hrs.The mixture was filtered, washed with cold IPA (95 mL) and tBME (160 mL)and dried to afford the title compound as a solid (62.5 g).

LCMS (Method A): 1.56 min, 177 [M+H]+

Preparation of 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinonitrile (Int 3)

Trimethylsilyl cyanide (56.3 g, 568 mmol) was added to Int 2 (50.0 g,284 mmol) in DCM (250 mL) at ambient temperature. The mixture wasstirred for 1 hr and then cooled to 10° C. Benzoyl chloride (59.8 g, 425mmol) was added and the mixture was heated to 40° C. and stirredovernight. The mixture was then poured into saturated aqueous NaHCO₃(750 mL). Triethylamine (7.5 mL) was added and the mixture stirred at40° C. overnight. The aqueous phase was separated and extracted with DCM(100 mL). The combined organics were washed with water (200 mL), driedover Na₂SO₄, filtered and concentrated to give the crude product. Thismaterial was stirred in hexane (504 mL) and ethyl acetate (56 mL)overnight. The product was filtered, washed with hexane (100 mL) anddried to give the title compound as a solid (48.7 g).

LCMS (Method A): 1.99 min, 186 [M+H]+

Preparation of 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid lithiumsalt (1:1) (Int 4)

Lithium hydroxide monohydrate (16.5 g, 393 mmol) in water (130 mL) wasadded to Int 3 (66.1 g, 357 mmol) in warm IPA (460 mL) and the mixturewas heated to 80° C. and stirred overnight. The mixture was thensubjected to azeotropic drying with additions of IPA. The resultingsuspension was stirred overnight at ambient temperature. The product wasfiltered, washing with IPA and dried to afford the title compound as asolid (67.8 g).

LCMS (Method A): 1.42 min, 205 [M+H]+ Preparation ofN-[(2S)-1-aminopropan-2-yl]-N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide(Int 11, Scheme 2)

Preparation of (2S)-1-methoxy-1-oxopropan-2-aminium chloride (Int 5)

To a solution of L-alanine (5.0 g, 56 mmol) in methanol (60 mL) at −20°C. was added dropwise thionyl chloride (6.1 mL, 84 mmol) and the mixturewas stirred at ambient temperature overnight. The solvent was removed invacuo. The solid residue was washed with diethyl ether, filtered anddried under vacuum to afford the title compound as a white solid (7.7g). The crude product was used without further purification insubsequent reactions.

1H NMR (500 MHz, d4-MeOH) δ 4.11 (q, 1 H), 3.84 (s, 3H), 1.54 (d, 3H).

Preparation of methyl (2S)-2-(benzylamino)-3-methylbutanoate (Int 6)

A mixture of benzaldehyde (2.9 mL, 28 mmol), Int 5 (5.9 g, 42 mmol),molecular sieves (5 g), and triethylamine (6.0 mL, 42 mmol) was stirredat ambient temperature for 6 hrs. NaBH(OAc)₃ (12 g, 56 mmol) was addedand the mixture stirred at ambient temperature for 16 hrs under anatmosphere of nitrogen. The mixture was diluted with DCM (100 mL),quenched with saturated aqueous NaHCO₃ and the phases were separated.The aqueous phase was extracted with DCM. The combined organic phaseswere washed with water, brine, dried over MgSO₄, filtered andconcentrated in vacuo to give the title compound as a colourless oil(3.2 g). The crude product was used without further purification insubsequent reactions.

LCMS (Method B): 1.33 min, 194 [M+H]+

1H NMR (500 MHz, CDCl₃) δ 7.35-7.30 (m, 4H), 7.26 (s, 1 H), 3.80 (d,1H), 3.73 (s, 3H), 3.67 (d, 1H), 3.40 (d, 1H), 1.32 (d, 3H).

Preparation of methyl (2S)-2-[benzyl(methyl)amino]propanoate (Int 7)

To a solution of Int 6 (1.5 g, 6.8 mmol) in DCE (35 mL) was addedmolecular sieves (1 g), an aqueous solution of formaldehyde (37%; 1.0mL, 14 mmol) and NaBH(OAc)3 (3.0 g, 14 mmol) and the mixture was stirredat ambient temperature for 1 hr. The solution was decanted and washedwith saturated aqueous NaHCO₃. The organic phase was dried over MgSO₄,filtered and concentrated in vacuo to afford the title compound as acolourless oil (1.3 g). The crude product was used without furtherpurification in subsequent reactions.

LCMS (Method B): 1.53 min, 208 [M+H]+

1H NMR (500 MHz, CDCl₃) δ 7.37-7.28 (m, 4H), 7.27-7.21 (m, 1 H), 3.73(s, 3H), 3.71 (s, 1H), 3.62 (d, 1H), 3.48 (q, 1H), 2.29 (s, 3H), 1.34(d, 3H).

Preparation of (2S)-2-[benzyl(methyl)amino]propan-1-ol (Int 8)

To an ice cooled solution of Int 7 (1.3 g, 5.9 mmol) in anhydrous THF(12 mL) was added dropwise LiAlH₄ (1M solution in THF; 12 mL, 12 mmol)and the mixture was stirred in an ice bath for 2 hrs. The mixture wasdiluted with diethyl ether and quenched by sequential addition of water(0.45 mL) followed by 2M aqueous NaOH (0.45 mL) and water (1.5 mL). Thephases were separated and the organic phase was dried over MgSO₄,filtered and concentrated in vacuo to give the title compound as acolourless oil (1.0 g). The crude product was used without furtherpurification in subsequent reactions.

LCMS (Method B): 1.37 min, 180 [M+H]+

1H NMR (500 MHz, CDCl₃) δ 7.35-7.28 (m, 4H), 7.28-7.23 (m, 1 H), 3.68(d, 1 H), 3.46 (d, 1H), 3.44-3.35 (m, 2H), 2.98 (dt, 1H), 2.15 (s, 3H),0.93 (d, 3H).

Preparation of tert-butylN-[(2S)-2-[benzyl(methyl)amino]propyl]carbamate (Int 9)

A mixture of Int 8 (0.61 g, 3.1 mmol), ethyl2-{[(tert-butoxy)carbonyl]amino}-2-oxoacetate (630 μl, 3.1 mmol) andtriphenylphosphine (0.88 g, 3.4 mmol) in anhydrous THF (20 mL) wascooled to −10° C. and treated with DEAD (0.48 mL, 3.1 mmol) by dropwiseaddition. The mixture was stirred at ambient temperature overnight. Thesolvent was removed in vacuo. The residue was poured onto brine / water(1:1, 20 mL) and extracted with diethyl ether. The combined organicphases were concentrated in vacuo. The residue was dissolved in THF (10mL), LiOH (0.32 g, 13 mmol) and water (10 mL) were added and the mixturewas stirred at ambient temperature for 2 hrs. The solvent was removed invacuo. The residue was poured onto water (50 mL) and extracted withdiethyl ether. The combined organic phases were concentrated in vacuo.The crude product was purified by chromatography on the Biotage IsoleraFour™ (25 g column, 0 to 100% EtOAc in heptane) to afford title compoundas a colourless oil (0.57 g).

LCMS (Method B): 1.88 min, 279 [M+H]+

1H NMR (500 MHz, CDCl₃) δ 7.31 (d, 4H), 7.26-7.22 (m, 1 H), 3.62 (d, 1H), 3.43 (d, 1 H), 3.27-3.17 (m, 1H), 3.01-2.93 (m, 1H), 2.89-2.80 (m,1H), 2.13 (s, 3H), 1.45 (s, 9H), 0.97 (d, 3H).

Preparation of tert-butyl N-[(2S)-2-(methylamino)propyl]carbamate (Int10)

A solution of Int 9 (0.57 g, 1.6 mmol) in methanol (40 mL) was passedtwice over a Pearlman's catalyst cartridge on the H-Cube® system(flow-rate of 1 mL/min, at 20 bar hydrogen pressure, at ambienttemperature). The mixture was concentrated in vacuo to afford the titlecompound as a colourless oil (0.4 g). The crude product was used withoutfurther purification in subsequent reactions.

1H NMR (500 MHz, CDCl₃) δ 3.72 (d, 1H), 3.47 (d, 1H), 3.45 (s, 3H),3.33-3.25 (m, 1H), 1.42 (s, 9H), 1.38 (d, 3H).

Preparation ofN-[(2S)-1-aminopropan-2-yl]-N,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide(Int 11)

To a solution of Int 10 (0.40 g, 1.6 mmol), Int 4 (0.39 g, 1.9 mmol) andDIPEA (0.83 mL, 4.8 mmol) in anhydrous DMF (7 mL) was added HATU (0.73g, 1.9 mmol) and the mixture was stirred at ambient temperature for 16hrs. The mixture was poured onto water (30 mL) and extracted with EtOAc.The combined organic phases were dried over MgSO₄, filtered andconcentrated in vacuo. The crude intermediate was purified bychromatography on the Biotage Isolera Four™ (25 g column, 0 to 100%EtOAc in heptane). The resulting intermediate was dissolved in HCl (4Min dioxane; 10 mL, 40 mmol) and stirred at ambient temperature for 1 hr.The solvent was removed in vacuo. 2M Aqueous sodium hydroxide was addedand the mixture extracted with EtOAc. The combined organic phases weredried over MgSO₄, filtered and concentrated in vacuo to afford the titlecompound as a yellow glass (0.37 g). The crude product was used withoutfurther purification in subsequent reactions.

LCMS (Method B): 1.19 min, 275 [M+H]+

1H NMR (500 MHz, d6-DMSO) δ 8.24 (dd, 1H), 8.12 (d, 2H), 7.54-7.51 (m,1H), 3.68-3.61 (m, 1H), 2.82 (s, 1H), 2.69 (s, 6H), 2.65 (s, 1H), 2.56(d, 3H).

Preparation ofN,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)-N[(2S)-1-{[5-(trifluoromethyl)pyrazin-2-yl]amino}propan-2-yl]pyridine-2-carboxamide (Example 1,Scheme 3

To a stirred solution of Int 11 (0.58 g, 2.1 mmol) in THF (2 mL) wasadded DIPEA (1.0 mL, 5.8 mmol) followed by2-chloro-5-(trifluoromethyl)pyrazine (0.39 g, 2.1 mmol) and the mixturewas heated at 70° C. for 4 hrs. The reaction mixture was allowed to coolto ambient temperature and allowed to stand over the weekend. Thereaction mixture was heated at 70° C. for a further 4 hrs with stirringand allowed to cool to ambient temperature. The reaction mixture wasevaporated in vacuo. The residue was purified by preparative HPLC(Column: Waters Xbridge C18 (10 μm, 30×100 mm). Conditions: Water +0.2%ammonium hydroxide [Eluent A]; MeCN+0.2% ammonium hydroxide [Eluent B].Gradient: 10 to 95% B) and then lyophilised to give title compound as awhite solid (0.32 g)

LCMS (Method C): Two peaks at 4.20 and 4.39 min, 421 [M+H]+

1H NMR (500 MHz, d4-MeOH) δ 8.38 (d, 0.15 H), 8.34 (bs, 0.15 H), 8.24(d, 0.85 H), 8.03 (bs, 0.85 H), 7.99 (s, 0.30 H), 7.97 (s, 1.70 H), 7.85(bs, 1.00 H), 7.57 (d, 0.15 H), 7.41 (d, 0.85 H), 4.98 (m, 0.15 H), 4.06(bm, 0.85 H), 3.50 (d, 0.15 H), 3.47 (d, 0.85 H), 3.42 (d, 0.85 H), 3.39(d, 0.15 H), 3.05 (s, 2.55 H), 2.83 (s, 0.45 H), 2.65 (s, 0.45 H), 2.45(bs, 2.55 H), 1.38 (d, 0.45 H), 1.07 (bs, 2.55 H).

Preparation ofN,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)-N[(2S)-1-{[5-(trifluoromethyl)pyrimidin-2-yl]amino}propan-2-yl]pyridine-2-carboxamide (Example2, Scheme 4)

To a stirred suspension of Int 11 (0.72 g, 2.5 mmol) in THF (10 mL) wasadded 2-chloro-5-(trifluoromethyl)pyrimidine (0.69 g, 3.8 mmol) followedby DIPEA (860 μl, 5.1 mmol).

The reaction mixture was stirred for 2 hrs at ambient temperature andthen at 30° C. for a further 3 hrs and then concentrated in vacuo. Thecrude product was dissolved in DMSO (9 mL) and purified by preparativeHPLC (Column: Waters Sunfire C18 (10 μm, 30×100 mm). Conditions:Water+0.1% formic acid [Eluent A]; MeCN+0.1% formic acid [Eluent B].Gradient: 10 to 95% B). The product was lyophilised from water (10 mL)and acetonitrile (2 mL) to give the title product as a white solid (0.51g). EtOAc (2 mL) was added to the solid and heated at 80° C. withstirring. Heptanes (6 mL) was added slowly to this refluxing solutionand allowed to cool to ambient temperature with stirring over 2 hrs. Thewhite solid was filtered and washed with a 20% solution of EtOAc inheptane (2 mL) and dried to give the title compound as a white solid(0.42 g).

LCMS (Method C): Two peaks at 3.07 and 3.18 min, 421 [M+H]+

1H NMR (500 MHz, CDCl3) δ 8.50 (bd, 0.60 H), 8.46 (s, 1.40 H), 8.26 (d,0.30 H), 8.17 (d, 0.70 H), 8.07 (s, 1.00 H), 7.93 (bs, 1.40 H), 7.87(bs, 0.60 H), 7.32 (d, 0.70 H), 7.30 (d, 0.30 H), 5.11 (bm, 0.30 H),4.13 (m, 0.70 H), 3.82 (m, 0.30 H), 3.64 (m, 0.70 H), 3.54 (m, 0.30 H),3.29 (dt, 0.70 H), 2.98 (s, 2.10 H), 2.80 (s, 0.90 H), 2.66 (s, 2.10 H),2.61 (s, 0.90 H), 1.36 (m, 3.00 H).

Alternative Methods for the Preparation of Example 1 Preparation of(2S)-N²-methyl-N¹-(5-(trifluoromethyl)pyrazin-2-yl)propane-1,2-diamine1,3,5-Benzenetricarboxvlic acid salt (Int 15, Scheme 5)

Preparation of (2S)-2-(benzyl(methyl)amino)propanamide (Int 12)

To a stirred suspension of (S)-2-aminopropanamide hydrochloride (1000 g,8028 mmol) in ethanol (7000 mL) was added sodium hydroxide (321 g, 8028mmol) followed by water (2000 mL) and benzaldehyde (854 mL, 8429 mmol).5% Palladium on carbon (J-M Type 58, 150 g) was added as a slurry inethanol (500 mL) and washed in with additional ethanol (500 mL). Themixture was vigorously agitated under an atmosphere of hydrogen at 3-3.5bar pressure for 24 hrs. Paraformaldehyde (603 g, 2014 mmol) was addedfollowed by 5% Palladium on carbon (J-M Type 58, 50 g) and the mixturevigorously agitated under an atmosphere of hydrogen at 3-3.5 barpressure for 17 hrs. The reaction mixture was filtered through a pad ofcelite and washed with ethanol (2×2000 mL). The filtrate wasconcentrated to an approximate volume of 2000 mL and the concentratedsolution partitioned between water (20000 mL) and tBME (20000 mL). Theorganic phase was collected and the aqueous extracted with further tBME(10000 mL). The organics were combined, concentrated to a volume ofapproximately 3000 mL and treated with heptane (12000 mL). The mixturewas heated to 70° C. and tBME (2000 mL) added portion wise until thesolution became clear. The solution was cooled and allowed to stand at0-5° C. for 20 hrs. The resulting solid was collected by filtration andwashed with cold heptane (5000 mL) to afford the title compound (835 g).

1H NMR (400 MHz, MeOD) δ 7.35-7.31 (m, 4H), 7.27-7.23 (m, 1 H), 3.60 (s,2H), 3.24 (q, 1H), 2.20 (s, 3H), 1.27 (d, 3H).

Preparation of (2S)-N²-benzyl-N²-methylpropane-1,2-diamine D-Tartaricacid salt (Int 13)

To a stirred solution of Int 12 (800 g, 4161 mmol) in anhydrous THF(6400 mL) under nitrogen at 0° C., was added LiAlH₄ (1 M in THF; 6242mL, 6242 mmol) maintaining the reaction mixture at a temperature below15° C. during the addition. The reaction mixture was warmed to 30° C.and stirred for 24 hrs before being cooled to 0° C. Water (224 mL),followed by a 15% solution of sodium hydroxide in water (224 mL) andthen water (672 mL) were added cautiously, maintaining the reactionmixture at a temperature below 15° C. The reaction mixture was warmed toambient temperature and tBME (2000 mL) was added and, after stirring for1 hr, the mixture was filtered through a pad of celite washing with THF(2×1600 mL). The filtrate was concentrated to a volume of approximately2400 mL and then THF (13600 mL) was added. The mixture was heated to 55°C. and a solution of D-tartaric acid (625 g, 4100 mmol) in methanol(2000 mL) added. The resulting suspension was stirred at 60-65° C. for 3hrs, then cooled to ambient temperature and stirred for a further 10hrs. The resulting solid was collected by filtration and washed with THF(2×6400 mL) to afford the title compound as a solid (1068 g).

1H NMR (500 MHz, d6-DMSO) δ 7.39 (d, 2H), 7.33 (t, 2H), 7.24 (t, 1 H),3.88 (s, 2H), 3.60 (d, 1 H), 3.48 (d, 1 H), 3.02-2.98 (m, 1H), 2.90-2.85(m, 1H), 2.78-2.75 (m, 1 H), 2.01 (s, 3H), 0.95 (d, 3H).

Preparation of(2S)-N²-methyl-N¹-(5-(trifluoromethyl)pyrazin-2-yl)propane-1,2-diamine(Int 14)

To a stirred mixture of tBME (6000 mL) and water (7000 mL) containingpotassium carbonate (1326 g, 9593 mmol) was added Int 13 (1050 g, 3198mmol) and water (1400 mL) followed by2-chloro-5-(trifluoromethy)pyrazine (584 g, 3198 mmol) and tBME (2400mL). The mixture was heated to 50° C. and stirred vigorously for 24 hrsthen cooled to ambient temperature. The organic phase was separated andwashed with water (4200 mL). Ethanol (3000 mL) was added to the organicsand the solution concentrated to a volume of approximately 3000 mL. Thisprocess was repeated twice more with ethanol (2100 mL and 5200 mL) andthe resulting concentrated solution was treated with 10% Palladium oncarbon (J-M Type 487, 260 g) as a slurry in ethanol (1000 mL) which waswashed in with further ethanol (6500 mL). The mixture was stirredvigorously under an atmosphere of hydrogen at 3-3.5 bar pressure and ata temperature of 40° C. for 16 hrs. The solution was then cooled toambient temperature and filtered through a pad of celite washing withethanol (2100 mL) and the filtrate concentrated to dryness to afford thetitle compound as an oil (684 g).

1H NMR (400 MHz, MeOD) δ 8.29 (s, 1 H), 7.97 (s, 1 H), 3.52 (dd, 1 H),3.43 (dd, 1 H), 2.96-2.90 (m, 1H), 2.44 (s, 3H), 1.16 (d, 3H).

Preparation of(2S)-N²-methyl-N¹-(5-(trifluoromethyppyrazin-2-yl)propane-1,2-diamine1,3,5-Benzenetricarboxylic acid salt (Int 15)

To a stirred solution of benzene-1,3,5-tricarboxylic acid (71 g, 342mmol) in ethanol (1600 mL) at 50° C. was added a solution of Int 14 (80g, 342 mmol) in ethanol (800 mL). The resulting solution was warmed to65-70° C. then stirred at this temperature for 3 hrs and at ambienttemperature for 16 hrs. The mixture was concentrated to a volume ofapproximately 800 mL, tBME (2000 mL) added and the resulting suspensionstirred vigorously for 16 hrs. The solid was collected by filtration andwashed with tBME (2×800 mL) to afford the title compound as a solid (123g).

1H NMR (400 MHz, MeOD) δ 8.78 (s, 3H), 8.34 (s, 1H), 8.05 (s, 1 H), 3.81(dd, 1H), 3.69 (dd, 1 H), 3.57-3.49 (m, 1H), 2.76 (s, 3H), 1.39 (d, 3H).

Preparation of(2S)-N²-methyl-N¹-(5-(trifluoromethyppyrazin-2-yl)propane-1,2-diamine(Int 14, Scheme 6)

To a white stirred suspension of Int 15 (10.6 g, 23.8 mmol) in EtOAc (50mL) was added a solution of potassium carbonate (9.9 g, 71 mmol) inwater (75 mL). The resulting bi-phasic mixture was stirred vigorously atambient temperature for 3 hrs. The organic phase was collected and theaqueous washed with EtOAc (2×50 mL). The combined organic extracts wereconcentrated to dryness to afford the title compound as an oil (4.69 g).

Preparation of 2-methyl-5-(2H-1,2,3-triazol-2-yl)pyridine (Int 1, Scheme1)

Int 1 may be prepared using the method described in Scheme 1 but with0.5 equivalents of copper powder.

Int 1 may be prepared using the method described in Scheme 1 but with 2equivalents of potassium carbonate.

Preparation ofN,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)-N-[(2S)-1-{[5-(trifluoromethyl)pyrazin-2-yl]amino}propan-2-yl]pyridine-2-carboxamide (Example 1,Scheme 7

To a stirred suspension of Int 4 (420 g, 1999 mmol) in EtOAc (4200 mL)under a nitrogen atmosphere was added thionyl chloride (438 mL, 5997mmol) over 5 mins. The temperature of the reaction was increased to 65°C. and the mixture stirred for 3 hrs at this temperature. Additionalthionyl chloride (73 mL, 999 mmol) was added and stirring continued for1 hr. Further thionyl chloride was added (73 mL, 1000 mmol) and thereaction stirred at 70° C. for 1 hr and then at ambient temperature for16 hrs. The reaction mixture was concentrated to dryness, EtOAc (4200mL) added and the process repeated. The residue was treated with EtOAc(8000 mL) and cooled to 0-5° C. under nitrogen. A solution oftriethylamine (557 mL, 3998 mmol) in EtOAc (800 mL) was added dropwisefollowed by the portion-wise addition of a solution of Int 14 (468 g,1999 mmol) in EtOAc (3200 mL) maintaining the reaction temperature at 0°C. The reaction was warmed to ambient temperature and stirred for 16hrs. Water (6300 mL) was added and the bi-phasic mixture filteredthrough a pad of Celite. The organic phase was collected, washed with asaturated aqueous solution of NaHCO3 (6300 mL) and water (3000 mL).Charcoal (43 g) was added to the organic extracts and the resultingblack suspension stirred for 24 hours at 50° C. The charcoal was removedby filtration through a pad of Celite and the filtrate concentrated toan approximate volume of 2100 mL. The concentrated solution was treatedwith EtOAc (2100 mL), water (1100 mL) and heptane (11000 mL) and theresulting suspension heated to 70° C. Further EtOAc (1600 mL) was addeduntil full dissolution was achieved. The reaction was allowed to cool toambient temperature and stirred for 16 hrs. The resulting precipitatewas collected by filtration, washed twice with heptane (4200 mL) anddried to afford the title compound as a solid (480 g).

Biological Assays

Antagonism against orexin receptors has been measured for each examplecompound using at least one of the following procedures. Antagonism isreported as a pIC₅₀, where pIC₅₀=—log₁₀(IC₅₀) and where IC₅₀ is theconcentration of example compound needed to inhibit 50% of the agonistresponse. These values may fluctuate depending on the daily cellularassay performance. Fluctuations of this kind are known to those skilledin the art. All reported values are the result of at least fourreplicate experiments. Ox2 values are only reported from dose responsecurves for which the top concentration is at least 10μM.

Ox1 and Ox2 Antagonist FLIPR Assay:

Test compounds are prepared as 20 mM stock solutions in DMSO, thenserially diluted in half log concentrations with DMSO followed bydilution with assay buffer (HBSS Gibco, 14065-049) containing 20mM HEPES(Gibco, 15630-56), 2.5mM Probenecid; 0,1% (w/v) pluronic F127(Sigma,P2443) and adjusted to pH 7.4) to a top final assay concentrationof 1 μM or 10 μM, depending on the potency at a given human OX receptor.

Human OX₁ or human OX₂ receptor expressing CHO cells are plated into 384well black, clear bottom, CellBIND plates at a seeding density of 10,000cells/75 μL growth media. The seeded plates are incubated at 37° C. inair supplemented with 5% CO₂ overnight.

The next day media is removed and replaced with 30 μL/well of cellloading buffer (a vial of Calcium 5 is solubilized in 20 mL of assaybuffer) and the cells incubated for 1 hr at 37° C. The serially dilutedtest compounds (10 μL/well) are added to the cell plate by the FLIPRTetra and the addition is monitored for 5 min by the instrument. Thecell plate is then removed and incubated for additional 25 min in ahumidified incubator at 37° C. prior to being placed back into the FLIPRTetra. Finally 10 pL of orexin Ain assay buffer +0.1% (w/v) bovine serumalbumin is dispensed by the FLIPR Tetra at an EC₇₅ concentrationdetermined for each receptor on the day of the assay. Fluorescence ismeasured at excitation and emission wavelengths of 485 nm and 525 nm,respectively and data analyzed using GraphPad Prism for the EC₇₅ valueof orexin A and Aplus to determine a pIC₅₀ value for each test compound.Established QC criteria (z′value and potency of pharmacologicalreference compounds) are applied to declare a plate as failed orapproved for database upload.

All reported values are the result of at least four replicates.

Ox2 values are only reported from dose response curves for which the topconcentration is at least 10μM.

Orexin 1 Receptor Radioligand Binding Assay:

Cell membranes were prepared from the human OX₁ receptor expressing CHOcell line. The harvested cell pellets were homogenized in ice-coldbuffer (15 mM TrisHCl (pH 7.5), 2 mM MgCl₂, 0.3 mM EDTA, 1 mM EGTA,Sigma protease inhibitor cocktail) and centrifuged at 41,000 g for 20min at 4° C. After discarding the supernatants the pellets werere-suspended in the before mentioned buffer followed by homogenizationand another centrifugation. Obtained pellets were re-suspended in icecold buffer containing 75 mM TrisHCl (pH 7.5), 12.5 mM MgCl₂, 0.3 mMEDTA, 1 mM EGTA, 250 mM sucrose and a protease inhibitor cocktail(Sigma). After protein quantification with the Pierce Protein Assay Kit,using BSA as standard, the membrane homogenates were aliquoted andfrozen down at 80° C. until further use.

Expression levels of the Ox1 receptor (Bmax) were determined bysaturation binding and the Kd of the radioligand [³H]SB674042 wasdetermined by association and dissociation kinetics. Data wereelaborated with Graph Pad Prism using radioligand binding analysis.Steady state binding was reached after 90 min of incubation at roomtemperature.

In competition binding experiments, 1 nM of [3H]-SB674042 was incubatedat room temperature for 90 min with 1.5 μg membrane protein andincreasing concentrations of displacing compounds in binding buffer (25mM HEPES pH7.3, 1 mM CaCl₂, 5 mM MgCl₂, 0.1% (w/v) BSA and 0.02% (w/v)pluronic acid) in a total assay volume of 200 μl. Reactions were stoppedby rapid filtration onto GF/B filters that have been pre-soaked with0.5% PEI. After filter drying, 30 μl/well of Microscint 0 are added, andthe radioactivity measured on a Microbeta counter (Perkin-Elmer). Datawere elaborated using Graph Pad Prism. The 50% inhibitory concentration(IC₅₀) obtained in competition binding experiments, using non-linearregression fitted to one-site model analysis was converted to Ki by theCheng—Prusoff equation, Ki=IC50/[1+([L]/Kd)], where [L] is the ligandconcentration and Kd the equilibrium dissociation constant (Cheng andPrusoff, 1973).

Orexin 2 Receptor Radioligand Binding Assay:

Cell membranes were prepared from the human Ox2 receptor expressing CHOcell line. The harvested cell pellets were homogenized in ice-coldbuffer (15 mM TrisHCl (pH 7.4), 2 mM MgCl₂, 0.3 mM EDTA, 1 mM EGTA,Sigma FAST™ protease inhibitor cocktail) and centrifuged at 45,000 rpmfor 30 min at 4° C. After discarding the supernatants the pellets werere-suspended in the before mentioned buffer followed by homogenizationand another centrifugation. Obtained pellets were re-suspended in icecold buffer containing 75 mM TrisHCl (pH 7.5), 12.5 mM MgCl₂, 0.3 mMEDTA, 1 mM EGTA, 250 mM sucrose and a Sigma FAST™ protease inhibitorcocktail. After protein quantification with the Pierce Protein AssayKit, using BSA as standard, the membrane homogenates were aliquoted andfrozen down at 80° C. until further use.

Expression levels of the Ox2 receptor (Bmax) were determined bysaturation binding and the Kd of the radioligand [³H]EMPA was determinedby association and dissociation kinetics. Data were elaborated withGraph Pad Prism using radioligand binding analysis. Steady state bindingwas reached after 60 min of incubation at room temperature.

In competition binding experiments, 2 nM of [3H]-EMPA was incubated atroom temperature for 60 min with 4 μg membrane protein and increasingconcentrations of displacing compounds in binding buffer (25 mM HEPESpH7.4, 1 mM CaCl₂, 5 mM MgCl₂, 0.5% (w/v) BSA and 0.05% (w/v) pluronicacid) in a total assay volume of 200 μl. Reactions were stopped by rapidfiltration onto GF/B filters that have been pre-soaked with 0.5% PEI.After filter drying, 30 μl/well of Microscint 0 are added, and theradioactivity measured on a Microbeta counter (Perkin-Elmer). Data wereelaborated using Graph Pad Prism. The 50% inhibitory concentration(IC50) obtained in competition binding experiments, using non-linearregression fitted to one-site model analysis was converted to Ki by theCheng—Prusoff equation, Ki=IC50/[1+([L]/Kd)], where [L] is the ligandconcentration and Kd the equilibrium dissociation constant (Cheng andPrusoff, 1973).

Example 1 Example 2 hOX1 pIC₅₀ 9.1 8.9 hOX2 pIC₅₀ 6.0 5.7 hOX1 pKi 9.08.8 hOX2 pKi 6.6 6.1

Kinetics of Competitive Binding (Motulski and Mahan's Analysis):

Motulsky and Mahan characterisation of the Examples was performed asdescribed by Faedo et al., European Journal of Pharmacology 692(2012),p.1-9 with the following modifications:

The association binding experiment was initiated by addition ofmembranes expressing the human Orexin 1 receptor at different times tothe incubation buffer containing 1 nM of [³H]SB674042. Non-specificbinding was determined in the presence of 10 μM of SB674042. Theassociation of the radioligand to the orexin receptor was performed asdescribed for the kinetics experiment in the presence of the competingtest compounds. The competing test compounds were assayed at threeconcentrations corresponding to 3, 10 and 30 fold of the determined Ki.For kinetic binding studies of the human Orexin 2 receptor, the methoddescribed for the Orexin 1 receptor was used with modifications thatmembranes expressing the human Orexin 2 receptor were incubated inbuffer containing 1 nM of [3H] EMPA and non-specific binding wasdetermined in the presence of 10 μM ACT-078573.

Orexin 1 Receptor Results

pKi K_(on) K_(off) (M&M) (M−1 min−1) (min−1) T_(1/2) (min) tR (min)Example 1^(a) 9.5 7.82E+06 0.003 248 357 Example 1^(b) 9.1 8.77E+060.007 104 150 Example 1^(c) 9.3 8.39E+06 0.005 170 245 Example 2^(a) 8.64.52E+06 0.010 67 96 Example 2^(d) 8.6 4.68E+06 0.011 60 87 Example2_(e) 8.6 4.57E+06 0.011 65 93 ^(a)Mean obtained from initial resultsusing the compound of Example 1 and Example 2 (n = 2) ^(b)Mean obtainedfrom further test results obtained using the compound of Example 1 (n =3) ^(c)Mean of all results obtained using the compound of Example 1 (n =5) ^(d)Further test result obtained using the compound of Example 2 (n= 1) ^(e)Mean of all results obtained using the compound of Example 2 (n= 3)

Orexin 2 Receptor Results:

pKi K_(on) K_(off) (M&M) (M−1 min−1) (min−1) T_(1/2) (min) tR (min)Example 1 6.5 6.46E+05 0.211 4.1 5.9 Example 2 5.8 1.10E+05 0.179 4.36.2

The results for the Orexin-2 Receptor studies are the mean of theresults from 3 studies (n=3) for both Example compounds.

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1. A compound which is selected fromN,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)-N-[(2S)-1-{[5-(trifluoromethyl)pyrazin-2-yl]amino}propan-2-yl]pyridine-2-carboxamide; andN,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)-N-[(2S)-1-{[5-(trifluoromethyl)pyrimidin-2-yl]amino}propan-2-yl]pyridine-2-carboxamide; or apharmaceutically acceptable salt or solvate thereof.
 2. A compoundaccording to claim 1, which isN,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)-N-[(2S)-1-{[5-(trifluoromethyl)pyrazin-2-yl]amino}propan-2-yl]pyridine-2-carboxamide; or apharmaceutically acceptable salt or solvate thereof.
 3. A compoundaccording to claim 1, which isN,6-dimethyl-3-(2H-1,2,3-triazol-2-yl)-N-[(2S)-1-{[5-(trifluoromethyl)pyrimidin-2-yl]amino}propan-2-yl]pyridine-2-carboxamide; or apharmaceutically acceptable salt or solvate thereof.
 4. A pharmaceuticalcomposition comprising a compound according to claim 2, or apharmaceutically acceptable salt or solvate thereof, and one or morepharmaceutically acceptable excipients. 5-6. (canceled)
 7. A method oftreating a disease or condition selected from schizophrenia and otherpsychotic disorders (e.g., psychotic disorder, psychosis orschizoaffective disorder); dementia and other cognitive disorders;anxiety disorders (e.g., generalized anxiety disorder, post-traumaticstress disorder, panic disorders, acute stress disorder, social anxietydisorder, phobias including agoraphobia, obsessive compulsive disorder,trichotillomania or body dysmorphic disorder); mood disorders (e.g.,depressive disorders, major depressive disorders, bipolar disordersincluding bipolar I and II, bipolar mania, bipolar depression);addiction including substance dependence (e.g., cocaine, opiates,cannabis or prescription drug dependence), alcohol dependence, nicotinedependence or gambling disorder; eating disorders (e.g., binge eating,bulimia nervosa, anorexia nervosa or obesity); sleep disorders (e.g.,rapid eye movement sleep disorder); disorders usually first diagnosed ininfancy, childhood, or adolescence (e.g., attention-deficit disorder,autistic spectrum disorders, Rett syndrome, Fragile X syndrome, Aspergersyndrome and disruptive behavior disorders); restless leg syndrome; pain(e.g., neuropathic pain including chemotherapy induced pain ormigraine); osteoporosis and neurodegenerative disorders (e.g.,Parkinson's or Alzheimer's disease), said method comprisingadministering to a subject in need of such treatment a therapeuticallyeffective amount of a compound according to claim 2, or apharmaceutically acceptable salt or solvate thereof.
 8. A pharmaceuticalcomposition comprising a compound according to claim 3, or apharmaceutically acceptable salt or solvate thereof, and one or morepharmaceutically acceptable excipients.
 9. A method of treating adisease or condition selected from schizophrenia and other psychoticdisorders (e.g., psychotic disorder, psychosis or schizoaffectivedisorder); dementia and other cognitive disorders; anxiety disorders(e.g., generalized anxiety disorder, post-traumatic stress disorder,panic disorders, acute stress disorder, social anxiety disorder, phobiasincluding agoraphobia, obsessive compulsive disorder, trichotillomaniaor body dysmorphic disorder); mood disorders (e.g., depressivedisorders, major depressive disorders, bipolar disorders includingbipolar I and II, bipolar mania, bipolar depression); addictionincluding substance dependence (e.g., cocaine, opiates, cannabis orprescription drug dependence), alcohol dependence, nicotine dependenceor gambling disorder; eating disorders (e.g., binge eating, bulimianervosa, anorexia nervosa or obesity); sleep disorders (e.g., rapid eyemovement sleep disorder); disorders usually first diagnosed in infancy,childhood, or adolescence (e.g., attention-deficit disorder, autisticspectrum disorders, Rett syndrome, Fragile X syndrome, Asperger syndromeand disruptive behavior disorders); restless leg syndrome; pain (e.g.,neuropathic pain including chemotherapy induced pain or migraine);osteoporosis and neurodegenerative disorders (e.g., Parkinson's orAlzheimer's disease), said method comprising administering to a subjectin need of such treatment a therapeutically effective amount of acompound according to claim 3, or a pharmaceutically acceptable salt orsolvate thereof.